ABSTRACT Recent evidence has provided an understanding of the molecular mechanisms and genetic changes underlying pancreatic ductal adenocarcinoma (PDAC) pathogenesis; however, limited information is available on progression in the disease. Studies in several genetically engineered mouse models for PDAC suggest that acinar cells, centroacinar cells, and/or postulated stem cells can be responsible for the development of PDAC. This is believed to occur via a process termed ?acinar-to-ductal metaplasia? (ADM), during which a differentiated cell type (acinar) is reversibly replaced with another mature, differentiated cell type, a condition also visible during inflammation, thereby underlining the predisposition of chronic pancreatitis patients to PDAC. Pancreatic differentiation 2 (PD2), also known as polymerase associated factor-1 (Paf1), has been found to be overexpressed in PDAC and to exhibit oncogenic potential. Our previous studies have further defined the role of PD2/Paf1 in cell cycle regulation and in inducing chromatin structure remodeling in PDAC cells. We have also demonstrated that PD2/Paf1 plays a major role in the multi-lineage differentiation of mouse embryonic stem cells and maintains pancreatic cancer stem cells (PCSCs). Our preliminary efforts to investigate the expression of PD2/Paf1 in KrasG12D;Pdx1Cre mouse model of PDAC showed that it is differentially overexpressed in neoplastic pancreatic ducts during murine PDAC progression, as compared to its strictly acinar expression in normal pancreas. PD2/Paf1 was specifically expressed in `intermediate structures' expressing both acinar and ductal specific markers, representing `transitional cells' during pancreatic acinar to ductal metaplasia. Further, we found that PD2/Paf1 is overexpressed along with PCSCs markers in PDAC progression in mouse tissues and isolated CSCs. The multi-potent property of these CSCs allows them to differentiate into several cell types. Therefore, the overall goal of this study is to define the role of PD2/Paf1 in trans-differentiation of acinar cells to ductal cells during PDAC progression, through lineage- differentiation of pancreatic CSC population. Based on these observations our central hypothesis is that ?PD2/Paf1 plays a significant role in the process of acinar-to-ductal metaplasia, thereby contributing to PDAC progression, and its overexpression contributes to the ductal lineage-differentiation of pancreatic CSCs.? To test this hypothesis, Aim 1 will focus on investigating the potential link of PD2/Paf1 in acinar-to-ductal metaplasia using cerulein-induced mouse model of PDAC progression. Aim 2 will elucidate the mechanism(s) of PD2/Paf1 in acinar-to-ductal metaplasia using acinar cells, organoid 3D-cultures, and PD2-/- animals. In Aim 3, we will understand the functional mechanism of PD2/Paf1 in ductal lineage-differentiation of pancreatic CSCs in PDAC progression. Taken together, understanding of novel roles of PD2/Paf1 in ADM progression through stem-like cell differentiation will lead to critical information for the long-term goal of developing novel, targeted therapy against PDAC.